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Apolipoprotein E4 genotype in combination with poor metabolic profile is associated with reduced cognitive performance in healthy postmenopausal women

implications for late onset Alzheimer's disease

Karim, Roksana, PhD, MBBS1,2; Koc, Melissa, BS1; Rettberg, Jamaica R., PhD3; Hodis, Howard N., MD1,2,4; Henderson, Victor W., MD5; St. John, Jan A., MPH1,2; Allayee, Hooman, PhD1; Brinton, Roberta D., PhD4,6,7; Mack, Wendy J., PhD1,2

doi: 10.1097/GME.0000000000001160
Original Articles

Objective: We hypothesized the association of metabolic profile on cognition in postmenopausal women will be greater among ApoE4 carriers compared with noncarriers.

Methods: Metabolic biomarkers and measures of global cognition, executive functions, and verbal memory, collected among postmenopausal females, were used in this analysis. Clustering analyses of metabolic biomarkers revealed three phenotypes: healthy, predominantly hypertensive, and poor metabolic with (borderline normal laboratory values). General linear models tested whether an association of metabolic cluster with cognition differed by ApoE4 genotype.

Results: In the total sample of 497 women, verbal memory was lower in the poor metabolic cluster (P = 0.04). Among ApoE4+ women, performance in all cognitive domains was lowest in the poor metabolic cluster. Differences in executive functions among metabolic clusters were detected only in ApoE4+ women (P value for interaction = 0.003).

Conclusions: In a general population of postmenopausal women, association between poor metabolic profile with reduction in cognitive performance is more apparent in women who carry an ApoE4 allele. These data indicate a window of opportunity for interventions to reverse the trajectory of the preclinical phase of Alzheimer's disease.

1Department of Preventive Medicine, University of Southern California, Los Angeles, CA

2Atherosclerosis Research Unit, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA

323andMe, Mountain View, CA

4Department of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Southern California, Los Angeles, CA

5Departments of Health Research and Policy (Epidemiology), and Neurology and Neurosciences, Stanford University, Stanford, CA

6Departments of Pharmacology & Neurology, College of Medicine, Center for Innovation in Brain Science, University of Arizona, Tucson, AZ

7Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA.

Address correspondence to: Roksana Karim, PhD, MBBS, USC Preventive Medicine, 2001 N Soto St., SSB 318D, Los Angeles, CA 90033. E-mail:

Received 14 February, 2018

Revised 14 May, 2018

Accepted 14 May, 2018

Funding/support: This work was supported by the National Institute of Health (grant numbers: P01AG026572, R01AG024154).

Financial disclosure/conflicts of interest: None reported.

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© 2019 by The North American Menopause Society.